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1. Project: Ghana Emergency Medicine Collaborative
Document Title: Sickle Cell Disease- Special Considerations in Pediatrics
Author(s): Hannah Smith, MD (Washington University in St. Louis)
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3. Sickle Cell Disease
Special Considerations in Pediatrics
Hannah Smith, MD
Washington University in St. Louis School of Medicine
3

4. Objectives
• Review pathophysiology of sickle cell disease
– Hemoglobin structure and function
• Recognize patient with sickle cell disease
• Understand major complications of sickle cell
disease and how to ameliorate or treat them
4

5. Disorders of Hemoglobin
Structure and Production
• Sickle hemoglobin syndromes
– Sickle cell anemia (SS)
– Hemoglobin S-hemoglobin C (SC) disease
– Hemoglobin S-β-thalassemia
• When hemoglobin S is <30% of the total
hemoglobin sickling is unlikely
5

6. Hemoglobin Structure and Production
• In the fetus:
– Hemoglobin F (α2γ2)
• After birth:
– Hemoglobin A (α2β2) – The most common with a
normal amount over 95%
– Hemoglobin A2(α2δ2) – δ chain synthesis begins late
in the third trimester and, in adults, it has a normal
range of 1.5–3.5%
– Hemoglobin F (α2γ2) – Typically very small
proportion, but Hb F can be elevated in persons with
sickle-cell disease and beta-thalassemia
6

7. Sickle Hemoglobin
7
OpenStax College (Wikimedia Commons)

8. Resistance to Malaria
• Sickled hemoglobin (even in heterozygotes)
gives resistance to Plasmodium falciparum
• Prevalence of sickle cell trait estimated to be
up to 40% where malaria is endemic
8

9. Hemoglobin Structure
• Sickle cell hemoglobin differs from normal hemoglobin by
a single amino acid
– Valine replaces glutamate on the surface of the Beta chain
• In sickled cells hemoglobin tetramers stick to each other,
forming long fibers (polymers) instead of remaining
independent
• These polymers distort RBCs into abnormal sickle shape
• Heterozygotes have a mixture of normal Hgb A and
abnormal Hgb S
– Hemoglobin A stops polymerization, preventing serious
sickling
• Red cell lysis occurs in homozygotes causing sickle cell
‘anemia’
9

10. Hemoglobin Structure
• Anemia is not present at birth but develops by 4
months of age as hemoglobin F is replaced by
hemoglobin S
• In the oxygenated state, hemoglobin S can
function normally, but when it is deoxygenated,
polymers more likely to form and lead to
distorted cell shape
• Sickle cells are destroyed and cause increased
blood viscosity, obstructing flow in small vessels
leading to crisis
10

11. Objectives
• Review pathophysiology of sickle cell disease
– Hemoglobin structure and function
• Recognize patient with sickle cell disease
• Understand major complications of sickle cell
disease and how to ameliorate or treat them
11

12. Sickle Cell Diagnosis
• Consider in children with:
– Unexplained pain or swelling (especially of hands
or feet)
– Pneumonia
– Meningitis
– Sepsis
– Neurologic abnormalities
– Splenomegaly
– Anemia
12

13. Sickle Cell Diagnosis
• Hemoglobin level and reticulocyte count are
inadequate screening tests
• Peripheral smear may lack sickled cells
• Hemoglobin electrophoresis definitive test
– Takes several days to result
13

14. Objectives
• Review pathophysiology of sickle cell disease
– Hemoglobin structure and function
• Recognize patient with sickle cell disease
• Understand major complications of sickle cell
disease and how to ameliorate or treat them
14

15. Major Complications
• Infections
– Particularly susceptible to encapsulated organisms
• Haemophilus influenza type b (Hib)
• Streptococcus pneumoniae (pneumococcus)
• Neisseria meningitidis (meningococcus)
• Group B streptococcus (GBS)
• Klebsiella pneumonia
• Salmonella typhi
• Sickle cell crises
– Vasoocclusive
– Sequestration or Aplastic
– Chronic organ damage 15

16. Major Complications
• Infections (GOAL: antibiotic therapy)
– Sepsis, meningitis, osteomyelitis, septic arthritis
• Sickle cell crises (GOAL: pain management, supportive care)
– Acute chest (treat as if associated infection – pneumonia)
– Vasoocclusive crisis
– Priapism
– Stroke (may be silent)
– Splenic sequestration
– Aplastic crisis
– Papillary necrosis
– Hepatobiliary crises
– Avascular necrosis
16

17. Sepsis
• Early loss of normal splenic activity
• Risk of bacterial sepsis increased several
hundredfold in comparison with normal population
– Pathogens in young children
• Streptococcus pneumonia and Haemophilus influenzae
– Pathogens in older children
• Escherichia coli and Salmonella
– Mortality from bacteremic episodes can be as high as 20-
30%
• Period of greatest risk between 6 months and 5
years when development of protective antibodies is
limited and splenic function is diminished or absent17

18. Sepsis
• Children with hemoglobin SC or SS disease are
prescribed prophylactic penicillin (or
erythromycin if penicillin allergy) through age
5 years to prevent S. pneumoniae sepsis
• Help prevent serious infections with vaccines
– Pneumococcal (S. pneumoniae)
– Hib (H. influenzae)
18

19. Sepsis
• Fever
– Must distinguish between SBI and benign, self-limiting viral
disorders
– All patients with sickle cell and fever should receive a basic
laboratory evaluation
• Malaria testing (when endemic)
• CBC
• Blood culture
• Consider: urine analysis, culture, throat culture
• Low threshold for obtaining a chest x-ray to screen for new
infiltrates
– Cornerstone of management in ED is rapid initiation of
antibiotics after obtaining appropriate cultures
19

20. Sepsis
• Disposition
– Routine admit, prolonged observation or outpatient
– General rule out sepsis admission practiced
– Close follow up at discharge, even after rule out
– Ampicillin or third-generation cephalosporin given IV
until culture results negative
– Young children (<2yo) are at higher risk of bacterial
sepsis and may be more difficult to assess for early
signs of sepsis than older children
– Temperatures >39-40°C suggest increased likelihood
of sepsis
20

21. Sepsis
• Treatment of ill-appearing child with sickle cell disease,
fever and probable sepsis, should include:
– Antibiotic therapy
– Management of septic shock
• Fluid resuscitation
• Pressors
• Clinical deterioration may be extremely rapid
• RBC transfusion or exchange transfusion may be
needed to correct severe anemia or reduce secondary
organ damage caused by massive sickling in presence
of hypoxia, stasis and acidosis
21

22. Infections
• Level of suspicion for meningitis should be
particularly high in the young, irritable child with
sickle cell disease and unexplained fever
• Septic arthritis and osteomyelitis can be a
diagnostic dilemma as mimics findings of
infarction of the bones (vasoocclusive crisis)
– The presence of other sites of concurrent infarction
and patient’s description of pain as typical “crisis pain”
may be helpful in identifying cause as vasooclusive
crisis
– Predisposition to Salmonella osteomyelitis may be
associated with areas of bone necrosis
22

23. Acute Chest Syndrome
• Includes pneumonia as well as pulmonary
infarction
• One of most common reasons for hospital
admission of children with sickle cell anemia
• Symptoms:
– Oxygen saturation below patient’s baseline
– Symptoms of respiratory distress
– New finding on chest radiograph
– Fever is often present
23

24. Acute Chest Syndrome
• Management:
– Antibiotic therapy
• Third-generation cephalosporin
• Macrolide
– Consideration of RBC transfusion
• Simple transfusion if hematocrit has fallen or is having evidence
of severe or rapidly progressive disease
• Exchange transfusion to decrease %HbS without raising
hematocrit
– *Treatment with steroids not usual part of regimen
unless patient has a history of asthma and signs of
asthma exacerbation
– Pain control
24

25. Vasoocclusive Crisis
• Management:
– Pain control
– General supportive measures
– Differentiation of vasoocclusion and disorders unrelated to
the hematologic abnormality
• Keys:
– Timely and efficient use of pain control early in the crisis
has been shown to decrease the length of hospital stays
– Initiation of PCA (patient controlled analgesia) in
appropriate patients while still in the ED
– Admission to the hospital warranted if continued pain
despite parenteral analgesia
• Prolonged stays in the ED rarely prevent hospital admissions
25

26. Vasoocclusive Crisis
• Dactylitis
– Between 6 and 24 months of age
– Recur frequently, caused by ischemic necrosis of small
bones
– Swelling may persist for 1-2 weeks, even after pain resolved
• Infarction of abdominal and retroperitoneal organs
– Hepatic infarct
• Acute onset of jaundice and abdominal pain similar to symptoms of
hepatitis, cholecystitis and biliary obstruction
• Pattern of recurrence important to indicate need for
cholecystectomy
• Occlusion of mesenteric vessels
– Mimics appendicitis/other cause of acute abdomen
26

27. Priapism
• Prolonged erection lasting >4h
• Penis is edematous and tender, urination may
be difficult
• Treatment:
– Fluid therapy and analgesia
– Early aspiration of the corpora
• Relationship between duration of priapism
and later potency in boys is unclear
27

28. Stroke
• Affects 7% of children with sickle cell disease
• Early detection of cerebral vascular disease
using transcranial Doppler screening may
reduce the frequency of stroke by allowing
preemptive use of long-term transfusion
therapy
• Routine screening for silent strokes
28

29. Stroke
• Presentation
– TIA to seizures to hemiparesis, coma and death
– Physical deficits supported by CT imaging
• Management of ischemic stroke
– IMMEDIATE 1.5 or 2-volume exchange transfusion as
soon as blood is ready
• Reduces likelihood of further intravascular sickling and may
prevent extension of cortical damage
– Long term transfusion therapy designed to maintain
HgbS to less than 30%
• Risk of recurrence is reduced from 70% within 3 years to 10-
15% with therapy
29

30. Stroke
• Risks of long term transfusion therapy
– Allosensitization
– Infection
– Iron overload
30

31. Stroke
• Alternative approaches
– Stem-cell transplantation
– Maintenance therapy with hydroxyurea
• Increases the level of HbF
• Prevents secondary stroke
31

32. Stroke
• Cerebral aneurysms occur in increased frequency
in patients with sickle cell disease
• Usually affects teens or adults
– May be related to local vessel damage
• Aneurysm often escapes detection until after
major and often fatal subarachnoid or
intracerebral bleeding
• Careful evaluation of patients with sickle cell
disease and headaches or other neurologic
findings (vertigo, syncope, nystagmus, ptosis,
meningismus or photophobia)
32

33. Stroke
• Management
– If aneurysm is accessible and bleeding persists,
surgical intervention follows radiologic
confirmation
33

34. Splenic Sequestration
• Life-threatening complication of sickle cell
disease
• Sudden enlargement of the spleen with resulting
sequestration of a substantial portion of the
blood volume
• Requires presence of vascularized splenic tissue,
so usually occurs before 5 years of age in patients
with hemoglobin SS disease, later in patients with
milder sickling disorders such as hemoglobin SC
or S-β0-thalassemia
34

35. Splenic Sequestration
• Presentation:
– Left upper quadrant pain
– Patient becomes pale, lethargic, disoriented and
appears ill
– Exam shows evidence of cardiovascular collapse,
hypotension and tachycardia are common; spleen is
enlarged from prior exam and hard
– Hematocrit and hemoglobin is lower than prior and
reticulocyte is increased
– Neutropenia or thrombocytopenia may be present
35

36. Splenic Sequestration
• Management:
– Early recognition is key
– Rapid infusion of large amounts of normal saline or
albumin to restore intravascular volume
– Transfusion with pRBCs (5 to 10mL/kg, beginning
carefully with 2 to 3mL/kg) is often required in more
severe cases
• Increases intravascular volume
• Improves impaired tissue oxygenation
– Reversal of shock and rising hematocrit signal
improvement of a sequestration crisis
• Spleen gradually becomes less firm and smaller
36

37. Aplastic Crisis
• Increased baseline bone marrow production
of RBCs (hence high retic count) partially
compensates for the shortened RBC survival in
sickle cell anemia
• When erythropoiesis slows or ceases, this
precarious balance is disturbed and
hemoglobin level may fall
37

38. Aplastic Crisis
• Parvovirus
– Most commonly causes erythroid aplasia
• Signs:
– Progressive pallor unaccompanied by jaundice or
other signs of hemolysis
– Severe anemia may result in dyspnea and alterations
in consciousness
• Laboratory
– Hemoglobin level is unusually low
– Reticulocytes are decreased or absent
38

39. Papillary Necrosis
• Hematuria that is usually sudden and painless,
often persistent
• Recent trauma, streptococcal infection or
recurrent UTI suggest other cause of hematuria
• Hypertension suggests presence of nephritis
rather than simple vasoocclusion
• Urine micro
– Abundant RBCs but no RBC casts
– Pyuria and proteinuria in excess of what might be
attributed to blood in urine are not present
39

40. Papillary Necrosis
• Management:
– Measure hematocrit
• If hematuria persistent, can precipitate drop in
hemoglobin
– Admission to hospital typically required for IV
hydration
– RBC transfusions are sometimes needed when
hematuria is severe
– Transfusions or exchange transfusions can be useful
in shortening the course of persistent hematuria
40

41. Hepatobiliary Crises
• Cholelithiasis is the most common hepatic and biliary tract
complication in children with sickle cell disease
– 12% in 2 to 5 year olds
– 40% by age 15 to 18
• Presentation:
– RUQ pain and tenderness , hyperbilirubinemia, and elevated
liver enzyme levels
• Treatment:
– Elective laproscopic cholecystectomy after preparations for
surgery (transfusions) and once acute inflammation has
subsided
• Acute cholecystectomy is associated with a significant risk
of complications
41

42. Hepatobiliary Crises
• Acute intrahepatic sickling or viral hepatitis
can result in similar clinical picture
– Massive hyperbilirubinemia
– Elevated enzyme levels
• Fulminant hepatic failure with hepatic
encephalopathy and shock can also occur as a
rare, often fatal syndrome
– Exchange transfusions may give some
improvement
42

43. Avascular Necrosis
• Sickle cell disease is the most common cause of
avascular necrosis of the femoral head in children
– Particularly Hgb SS and coexisting α-thalassemia
• Older children experience pain crises in long bones and the
back resulting in aseptic necrosis of the bone
• More common if hematocrit is high and the clinical course
is severe, with frequent painful crises
• Treatment:
– Options limited – bed rest, core decompression
– Total hip replacement may be necessary for femoral
avascular necrosis
43

44. Questions?
44

45. Sources
• Manual of Tropical Pediatrics. M.D. Seear. 2000.
• Textbook of Pediatric Emergency Medicine.
Fleisher and Ludwig. 2010.
45